This invention relates to compounds of formula I, which may be useful for treating diseases or conditions caused by or exacerbated by histamine-3 receptor activity, pharmaceutical compositions containing compounds of formula I and methods of treatment using compounds of formula I.
Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or xe2x80x9cantihistamines.xe2x80x9d It has also been established that histamine receptors exist in at least two distinct types, referred to as H1 and H2 receptors.
A third histamine receptor (H3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)). The existence of the H3 receptor has been confirmed by the development of selective H3 receptor agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
A number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H3 ligand may be an antagonist, agonist or partially agonist, see: (Imamura et al., Circ.Res., (1996) 78, 475-481); (Imamura et. al., Circ. Res., (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsychopharmacology (1996) 15, 31-35); (Sakai, et al., Life Sci. (1991) 48, 2397-2404); (Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Panula, P. et al., Neuroscience (1998) 44, 465-481); (Wada et al., Trends in Neuroscience (1991) 14, 415); (Monti et al., Eur. J. Pharmacol. (1991) 205, 283); (Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193-198); (Kamei et al., Psychopharmacology (1990) 102, 312-318); (Kamei and Sakata, Jpn. J. Pharmacol. (1991) 57, 437-482); (Schwartz et al., Psychopharmacology; The fourth Generation of Progress. Bloom and Kupfer (eds). Raven Press, New York, (1995) 397); (Shaywitz et al., Psychopharmacology (1984) 82,73-77); (Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69); (Tedford et al., J. Pharmacol. Exp. Ther. (1995) 275, 598-604); (Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22); (Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129); (Yokoyama and Iinuma, CNS Drugs (1996) 5, 321); (Onodera et al., Prog. Neurobiol. (1994) 42, 685); (Leurs and Timmerman, Prog. Drug Res. (1992) 39, 127); (The Histamine H3 Receptor, Leurs and Timmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci. (1998) 19, 177-183); (Phillips et al., Annual Reports in Medicinal Chemistry (1998) 33, 31-40); (Matsubara et al., Eur. J. Pharmacol. (1992) 224, 145); (Rouleau et al., J. Pharmacol. Exp. Ther. (1997) 281, 1085); (Adam Szelag, xe2x80x9cRole of histamine H3-receptors in the proliferation of neoplastic cells in vitroxe2x80x9d, Med. Sci. Monit., 4(5): 747-755, (1998)); (Fitzsimons, C., H. Duran, F. Labombarda, B. Molinari and E. Rivera, xe2x80x9cHistamine receptors signalling in epidermal tumor cell lines with H-ras gene alterationsxe2x80x9d, Inflammation Res., 47 (Suppl 1): S50-S51, (1998)); (R. Leurs, R. C. Vollinga and H. Timmerman, xe2x80x9cThe medicinal chemistry and therapeutic potentials of ligand of the histamine H3 receptorxe2x80x9d, Progress in Drug Research 45: 170-165, (1995)); (R. Levi and N. C. E. Smith, xe2x80x9cHistamine H3-receptors: A new frontier in myocardial ischemiaxe2x80x9d, J. Pharm. Exp. Ther., 292: 825-830, (2000)); (Hatta, E., K Yasuda and R. Levi, xe2x80x9cActivation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocradial ischemiaxe2x80x9d, J. Pharm. Exp. Ther., 283: 494-500, (1997); (H. Yokoyama and K. Iinuma, xe2x80x9cHistamine and Seizures: Implications for the treatment of epilepsyxe2x80x9d, CNS Drugs, 5(5); 321-330, (1995)); (K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, AQ-0145, xe2x80x9cA newly developed histamine H3 antagonist, decreased seizure susceptibility of eletrically induced convulsions in micexe2x80x9d, Meth. Find. Exp. Clin. Pharmacol., 17(C): 70-73, (1995); (Delaunois A., Gustin P., Garbarg M., and Ansay M., xe2x80x9cModulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungsxe2x80x9d, European Journal of Pharmacology 277(2-3):243-50, (1995)); and (Dimitriadou, et al., xe2x80x9cFunctional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleenxe2x80x9d, Clinical Science. 87(2):151-63, (1994). Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer""s disease and attention-deficit hyperactivity disorder; neurological disorders such as Parkinson""s disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere""s disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
WO 00/06254 describes non-imidazole alkylamines as histamine-3 receptor ligands. EP 0 978 512 A1 describes non-imidazole aryloxy alkylamines as histamine-3 receptor ligands.
In its principle embodiment, the present invention discloses compounds of formula I: 
or a pharmaceutically acceptable salt thereof, wherein
Z is selected from a covalent bond or CH2;
R1 is selected from OR2, NR3R4 or 
R2 is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, sulfono or phosphono;
R3 and R4 are independently selected from hydrogen, alkenyl, alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl, aminosulfonyl, arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl, arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, formyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclealkylsulfonyl, heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl, heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl, heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl, heterocycleoxyarylsulfonyl, heterocyclesulfonyl, or heterocyclethioalkylcarbonyl;
R5 and R6 are independently selected from hydrogen or alkyl;
R7 is selected from hydrogen or alkyl; or
R1 and R7 together form (xe2x95x90O);
R8 is selected from alkylcarbonyl, aryl, arylcarbonyl, arylcarbonylaryl, arylcarbonylheterocycle, cycloalkylcarbonyl, cycloalkylcarbonylaryl, cycloalkylcarbonylheterocycle, heterocycle, heterocyclecarbonyl, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle;
R9 is selected from the hydrogen or lower alkyl; and
RA, RB, RC and RD are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto or nitro.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principle embodiment, the present invention discloses compounds of formula I: 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein
Z is selected from a covalent bond or CH2;
R1 is selected from OR2, NR3R4 or 
R2 is selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, sulfono and phosphono; R3 and R4 are independently selected from hydrogen, alkenyl, alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl, aminosulfonyl, arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl, arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, formyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclealkylsulfonyl, heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl, heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl, heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl, heterocycleoxyarylsulfonyl, heterocyclesulfonyl or heterocyclethioalkylcarbonyl;
R5 and R6 are independently selected from hydrogen or alkyl;
R7 is selected from hydrogen or alkyl; or
R1 and R7 together form (xe2x95x90O);
R8 is selected from alkylcarbonyl, aryl, arylcarbonyl, arylcarbonylaryl, arylcarbonylheterocycle, cycloalkylcarbonyl, cycloalkylcarbonylaryl, cycloalkylcarbonylheterocycle, heterocycle, heterocyclecarbonyl, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle;
R9 is selected from hydrogen or lower alkyl; and
RA, RB, RC and RD are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto or nitro;
wherein at each occurrence of said aryl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl, arylcarbonylaryl, arylcarbonylheterocycle, arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl, arylsulfonyl, cycloalkylcarbonylaryl, heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonylaryl, heterocycleoxyarylcarbonyl, and heterocycleoxyarylsulfonyl, the aryl portion can be optionally substituted with 1, 2, or 3 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto or nitro; and
wherein at each occurrence of said arylcarbonylheterocycle, arylheterocylecarbonyl, arylheterocylesulfonyl, cycloalkylcarbonylheterocycle, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclealkylsulfonyl, heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl, heterocyclecarbonylaryl, heterocyclecarbonylheterocycle, heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl, heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl, heterocycleoxyarylsulfonyl, heterocyclesulfonyl, and heterocyclethioalkylcarbonyl, the heterocycle portion can be optionally substituted with 1, 2, or 3 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto or nitro.
In a preferred embodiment, compounds of the present invention have formula I wherein R1 is NR3R4; R3 and R4 are independently selected from hydrogen, alkenyl, alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl, aminosulfonyl, arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl, arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclealkylsulfonyl, heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl, heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl, heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl, heterocycleoxyarylsulfonyl, heterocyclesulfonyl or heterocyclethioalkylcarbonyl; R7 is hydrogen; R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; and Z, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula I wherein R1 is NR3R4; R3 and R4 are independently selected from hydrogen, alkenyloxycarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, arylalkenylsulfonyl, arylcarbonyl, arylsulfonyl, cycloalkylcarbonyl, heterocyclecarbonyl, heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl, heterocycleoxyarylsulfonyl, heterocyclesulfonyl, and heterocyclethioalkylcarbonyl; R7 is hydrogen; R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; and Z, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula I wherein Z is CH2; R1 is NR3R4; R3 and R4 are independently selected from hydrogen, alkoxycarbonyl or alkyl; R7 is hydrogen; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen.
In another preferred embodiment, compounds of the present invention have formula I wherein Z is a covalent bond; R1 is NR3R4; R3 and R4 are independently selected from hydrogen, alkoxycarbonyl or alkyl; R7 is hydrogen; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen.
In another preferred embodiment, compounds of the present invention have formula II 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein R10 is selected from alkenyl, alkyl, alkynyl, amino, aryl, arylalkenyl, arylalkyl, arylaryl, arylheterocycle, aryloxyaryl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclearyl, heterocycleheterocycle or heterocycleoxyaryl; and Z, R3, R8, R9 RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein R3 is selected from hydrogen or alkyl; R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; R10 is selected from alkyl, amino, aryl, arylalkenyl, heterocycle, heterocycleheterocycle or heterocycleoxyaryl; and Z, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula II wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen; and R10 is selected from alkyl or amino.
In another preferred embodiment, compounds of the present invention have formula II wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen; and R10 is aryl wherein said aryl is phenyl optionally substituted with 1 or 2 substitutuents selected from alkoxy, alkyl, alkylsufonyl, amino, cyano, haloalkoxy, haloalkyl or halogen.
In another preferred embodiment, compounds of the present invention have formula II wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen; and R10 is arylalkenyl wherein the aryl portion of said arylalkenyl is phenyl.
In another preferred embodiment, compounds of the present invention have formula II wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen; and R10 is heterocycle wherein said heterocycle is selected from benzothienyl, imidazolyl, isoquinolinyl, pyridinyl, pyrrolyl, quinolinyl, thiazolyl or thienyl, wherein said benzothienyl, imidazolyl, isoquinolinyl, pyridinyl, pyrrolyl, quinolinyl, thiazolyl or thienyl is optionally substituted with 1 or 2 substitutuents selected from alkoxy, alkyl, amino, haloalkyl or halogen.
In another preferred embodiment, compounds of the present invention have formula II wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R8 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or hydrogen; and R10 is heterocycleheterocycle wherein said heterocycleheterocycle is (3-chloro-5-(trifluoromethyl)-2-pyridinyl)-1H-pyrrol-2-yl.
In another preferred embodiment, compounds of the present invention have formula II wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are indepoendently selected from hydrogen or halogen; and R10 is heterocycleoxyaryl wherein said heterocycleoxyaryl is (3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenyl).
In another preferred embodiment, compounds of the present invention have formula III 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein R11 is selected from hydrogen, alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, alkynyloxy, amino, aryl, arylalkenyl, arylalkyl, arylaryl, arylheterocycle, aryloxyaryl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclearyl, heterocycleheterocycle, heterocycleoxyalkyl, heterocycleoxyaryl or heterocyclethioalkyl; and Z, R3, R8, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein R3 is selected from hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, and heterocyclecarbonyl; R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl and heterocyclecarbonylheterocycle; and R11 is selected from alkenyloxy, alkoxy, alkyl, amino, aryl, cycloalkyl, heterocycle, heterocycleheterocycle or heterocyclethioalkyl; and Z, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula III wherein Z is CH2; R3 is selected from hydrogen, alkyl, alkylcarbonyl, and aminocarbonyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen; and R11 is selected from alkenyloxy, alkoxy, alkyl, amino or cycloalkyl.
In another preferred embodiment, compounds of the present invention have formula III wherein Z is CH2; R3 is selected from hydrogen, alkyl or arylcarbonyl wherein the aryl portion of said arylcarbonyl is phenyl optionally substituted with 1 substituent selected from cyano or halogen; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; RA, RB, RC and RD are independently selected from hydrogen or halogen; and R11 is aryl wherein said aryl is phenyl optionally substituted with 1 substituent selected from cyano or halogen.
In another preferred embodiment, compounds of the present invention have formula III wherein Z is CH2; R3 is selected from hydrogen, alkyl or heterocyclecarbonyl wherein the heterocycle portion of said heterocyclecarbonyl is selected from 4-morpholinyl or 1-pyrrolidinyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; RA, RB, RC and RD are independently selected from hydrogen or halogen; and R11 is heterocycle wherein said heterocycle is selected from furyl, 4-morpholinyl, pyridinyl or pyrrolidinyl.
In another preferred embodiment, compounds of the present invention have formula III wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; RA, RB, RC and RD are independently selected from hydrogen or halogen; and R11 is heterocycleheterocycle wherein said heterocycleheterocycle is 2-(3-pyridinyl)-1,3-thiazol-4-yl.
In another preferred embodiment, compounds of the present invention have formula III wherein Z is CH2; R3 is selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; RA, RB, RC and RD are independently selected from hydrogen or halogen; and R11 is heterocyclethioalkyl wherein said heterocyclethioalkyl is [(4-methyl-2-pyrimidinyl)sulfanyl]methyl.
In another preferred embodiment, compounds of the present invention have formula IV 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein R3 and R4 are independently selected from hydrogen, alkenyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle or heterocyclealkyl; and Z, R8, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein R3 and R4 are independently selected from hydrogen or alkyl; R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; and Z, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula IV wherein Z is CH2; R3 and R4 are independently alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen, alkoxy, alkyl or halogen.
In another preferred embodiment, compounds of the present invention have formula IV wherein Z is CH2; R3 and R4 are independently selected from hydrogen or alkyl; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; and R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen.
In another preferred embodiment, compounds of the present invention have formula IV wherein Z is CH2; R3 and R4 are independently alkyl; R9 is 4-cyanophenyl; R9, RB, RC and RD are hydrogen; and RA is selected from alkoxy, alkyl or halogen.
In another preferred embodiment, compounds of the present invention have formula IV wherein Z is CH2; R3 and R4 are independently alkyl; R8 is 4-cyanophenyl; R9, RA, RC and RD are hydrogen; and RB is alkyl.
In another preferred embodiment, compounds of the present invention have formula IV wherein Z is CH2; R3 and R4 are independently alkyl; R9 is 4-cyanophenyl; R9, RB and RC are hydrogen; and RA and RD are independently halogen.
In another preferred embodiment, compounds of the present invention have formula V 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein Z, R2, R7, R8, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula V wherein R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; and Z, R2, R7, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula V wherein Z is CH2; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; RA, RB, RC and RD are independently selected from hydrogen or halogen; and R2 and R7 are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula VI 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein Z, R8, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula VI wherein R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; Z, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula VI wherein Z is CH2; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; and RA, RB, RC and RD are independently selected from hydrogen or halogen.
In another preferred embodiment, compounds of the present invention have formula VII 
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein Z, R5, R6, R8, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula VII wherein R8 is selected from alkylcarbonyl, cycloalkylcarbonyl, aryl, heterocycle, heterocyclecarbonylaryl or heterocyclecarbonylheterocycle; Z, R5, R6, R9, RA, RB, RC and RD are as defined in formula I.
In another preferred embodiment, compounds of the present invention have formula VII wherein Z is CH2; R8 is selected from acetyl, propionyl, cyclopropylcarbonyl, 4-cyanophenyl, 4-cyano-3-methylphenyl, 4-cyano-2-methylphenyl, 4-cyano-3-fluorophenyl, 2-pyridinyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)phenyl or 4-(1-piperazinylcarbonyl)-1-piperazinyl; R9 is hydrogen; RA, RB, RC and RD are independently selected from hydrogen or halogen; and R5 and R6 are as defined in formula I.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of modulating the effects of the histamine-3 receptor by agonism of the histamine-3 receptor in a mammal comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of modulating the effects of the histamine-3 receptor by antagonism of the histamine-3 receptor in a mammal comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, Meniere""s disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson""s disease, schizophrenia, seizures, septic shock, Tourette""s syndrome, vertigo, or wakefulness comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating mild cognitive impairment, deficits of memory, deficits of learning and dementia comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
The term xe2x80x9calkenylcarbonyl,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkenylcarbonyl include, but are not limited to, 3-butenoyl, 3-pentenoyl, and 4-pentenoyl.
The term xe2x80x9calkenyloxy,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy, and 3-butenyloxy.
The term xe2x80x9calkenyloxycarbonyl,xe2x80x9d as used herein, refers to an alkenyloxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkenyloxycarbonyl include, but are not limited to, allyloxycarbonyl, 2-butenyloxycarbonyl, and 3-butenyloxycarbonyl.
The term xe2x80x9calkenylsulfonyl,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkenylsulfonyl include, but are not limited to, allylsulfonyl, 2butenylsulfonyl, and 3-butenylsulfonyl.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, ethylsulfonyl, isopropylsulfonyl, and methylsulfonyl.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term xe2x80x9calkynylcarbonyl,xe2x80x9d as used herein, refers to an alkynyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkynylcarbonyl include, but are not limited to, 3-butynoyl, 3-pentynoyl, and 4-pentynoyl.
The term xe2x80x9calkynyloxy,xe2x80x9d as used herein, refers to an alkynyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkynyloxy include, but are not limited to, 2-butynyloxy, and 3-butynyloxy.
The term xe2x80x9calkynyloxycarbonyl,xe2x80x9d as used herein, refers to an alkynyloxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkynyloxycarbonyl include, but are not limited to, 2-butynyloxycarbonyl, and 3-butynyloxycarbonyl.
The term xe2x80x9calkynylsulfonyl,xe2x80x9d as used herein, refers to an alkynyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkynylsulfonyl include, but are not limited to, 2-butynylsulfonyl, and 3-butynylsulfonyl.
The term xe2x80x9camino,xe2x80x9d as used herein, refers to a xe2x80x94NRARB group wherein RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl, and benzyl. Representative examples of amino include but are not limited to acetylamino, amino, benzylamino, dimethylamino, and methylamino.
The term xe2x80x9caminoalkyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminoalkyl include, but are not limited, (amino)methyl, (dimethylamino)methyl, 2-(benzylamino)ethyl, and (ethylamino)methyl.
The term xe2x80x9caminocarbonyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of aminocarbonyl include, but are not limited, aminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl, and ethylaminocarbonyl.
The term xe2x80x9caminosulfonyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of aminosulfonyl include, but are not limited, aminosulfonyl, dimethylaminosulfonyl, benzylaminosulfonyl, and ethylaminosulfonyl.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic-ring system, or a bicyclic- or a tricyclic-fused ring system wherein one or more of the fused rings are aromatic. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
The aryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro.
The term xe2x80x9carylalkenyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of arylalkenyl include, but are not limited to, 3-phenyl-1-propenyl, and 2-(2-naphthyl)ethenyl.
The term xe2x80x9carylalkenylcarbonyl,xe2x80x9d as used herein, refers to an arylalkenyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkenylcarbonyl include, but are not limited to, 4-phenyl-3-butenoyl, and 3-phenyl-2-propenoyl.
The term xe2x80x9carylalkenylsulfonyl,xe2x80x9d as used herein, refers to an arylalkenyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylalkenylsulfonyl include, but are not limited to, 2-phenylethenylsulfonyl, and 4-phenyl-3-butenylsulfonyl.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term xe2x80x9carylalkylcarbonyl,xe2x80x9d as used herein, refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkylcarbonyl include, but are not limited to, phenylacetyl, 4-phenylbutanoyl, and 3-phenylpropanoyl.
The term xe2x80x9carylalkylsulfonyl,xe2x80x9d as used herein, refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylalkylsulfonyl include, but are not limited to, (2-phenylethyl)sulfonyl, and (3-phenylpropyl)sulfonyl.
The term xe2x80x9carylaryl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through another aryl group, as defined herein. Representative examples of arylaryl include, but are not limited to, (1,1xe2x80x2-biphenyl), and (2xe2x80x2-chloro(1,1xe2x80x2-biphenyl)-3-yl).
The term xe2x80x9carylarylcarbonyl,xe2x80x9d as used herein, refers to an arylaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylarylcarbonyl include, but are not limited to, (1,1xe2x80x2-biphenyl)carbonyl, and (2xe2x80x2-chloro(1,1xe2x80x2-biphenyl)-3-yl)carbonyl.
The term xe2x80x9carylarylsulfonyl,xe2x80x9d as used herein, refers to an arylaryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylarylsulfonyl include, but are not limited to, (1,1xe2x80x2-biphenyl)sulfonyl, and (2xe2x80x2-chloro(1,1 xe2x80x2-biphenyl)-3-yl)sulfonyl.
The term xe2x80x9carylcarbonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl, 4-cyanobenzoyl, and naphthoyl.
The term xe2x80x9carylcarbonylaryl,xe2x80x9d as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an aryl group, as defined herein. Representative examples of arylcarbonylaryl include, but are not limited to, 4-(benzoyl)phenyl and 4-(benzoyl)naphthyl.
The term xe2x80x9carylcarbonylheterocycle,xe2x80x9d as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through a heterocycle group, as defined herein. Representative examples of arylcarbonylheterocycle include, but are not limited to, 4-benzoyl-1-piperazinyl and 1-benzoyl-4-piperidinyl.
The term xe2x80x9carylheterocycle,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a heterocycle group, as defined herein. Representative examples of arylheterocycle include, but are not limited to, 5-phenylpyridin-2-yl and 5-(3-chlororphenyl)pyridin-2-yl.
The term xe2x80x9carylheterocyclecarbonyl,xe2x80x9d as used herein, refers to an arylheterocycle group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylheterocyclecarbonyl include, but are not limited to, 5-phenylpyridin-2-ylcarbonyl and 5-(3-chlororphenyl)pyridin-2-ylcarbonyl.
The term xe2x80x9carylheterocyclesulfonyl,xe2x80x9d as used herein, refers to an arylheterocycle group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylheterocyclesulfonyl include, but are not limited to, 5-phenylpyridin-2-ylsulfonyl and 5-(3-chlororphenyl)pyridin-2-ylsulfonyl.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.
The term xe2x80x9caryloxyaryl,xe2x80x9d as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an aryl group, as defined herein. Representative examples of aryloxyaryl include, but are not limited to, 3-(3-methylphenoxy)phenyl, and 3-(3-bromophenoxy)phenyl.
The term xe2x80x9caryloxyarylcarbonyl,xe2x80x9d as used herein, refers to an aryloxyaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of aryloxyarylcarbonyl include, but are not limited to, 3-(3-methylphenoxy)benzoyl, and 3-(3-bromophenoxy)benzoyl.
The term xe2x80x9caryloxyarylsulfonyl,xe2x80x9d as used herein, refers to an aryloxyaryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of aryloxyarylsulfonyl include, but are not limited to, 3-(3-methylphenoxy)phenylsulfonyl, and 3-(3-bromophenoxy)phenylsulfonyl.
The term xe2x80x9carylsulfonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, (4-acetylaminophenyl)sulfonyl, (4-chlorophenyl)sulfonyl, (4-cyanophenyl)sulfonyl, (4-methoxyphenyl)sulfonyl, (4-methylphenyl)sulfonyl, and (4-(tert-butyl)phenyl)sulfonyl.
The term xe2x80x9carylthio,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of arylthio include, but are not limited to, phenylsulfanyl, naphth-2-ylsulfanyl, and 5-phenylhexylsulfanyl.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
The term xe2x80x9ccycloalkylalkylcarbonyl,xe2x80x9d as used herein, refers to cycloalkylalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylalkylcarbonyl include, but are not limited to, cyclopropylmethylcarbonyl, 2-cyclobutylethylcarbonyl, cyclopentylmethylcarbonyl, cyclohexylmethylcarbonyl, and 4-cycloheptylbutylcarbonyl.
The term xe2x80x9ccycloalkylalkylsulfonyl,xe2x80x9d as used herein, refers to cycloalkylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of cycloalkylalkylsulfonyl include, but are not limited to, cyclopropylmethylsulfonyl, 2-cyclobutylethylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl, and 4-cycloheptylbutylsulfonyl.
The term xe2x80x9ccycloalkylcarbonyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.
The term xe2x80x9ccycloalkylcarbonylaryl,xe2x80x9d as used herein, refers to a cycloalkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an aryl group, as defined herein. Representative examples of cycloalkylcarbonylaryl include, but are not limited to, 4-(cyclopropylcarbonyl)phenyl, 4-(cyclopentylcarbonyl)phenyl, and 4-(cyclohexylcarbonyl)phenyl.
The term xe2x80x9ccycloalkylcarbonylheterocycle,xe2x80x9d as used herein, refers to a cycloalkylcarbonyl group, as defined herein, appended to the parent molecular moiety through a heterocycle group, as defined herein. Representative examples of cycloalkylcarbonylheterocycle include, but are not limited to, 4-(cyclopropylcarbonyl)-1-piperazinyl, 4-(cyclopentylcarbonyl)-1-piperazinyl, and 4-(cyclohexylcarbonyl)-1-piperazinyl.
The term xe2x80x9ccycloalkylsulfonyl,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of cycloalkylsulfonyl include, but are not limited to, cyclopropylsulfonyl, cyclopentylsulfonyl, and cyclohexylsulfonyl.
The term xe2x80x9cformyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic,xe2x80x9d as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl, pyranopyridyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridyl.
The heterocycles of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro.
The term xe2x80x9cheterocyclealkyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyl.
The term xe2x80x9cheterocyclealkylcarbonyl,xe2x80x9d as used herein, refers to a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclealkylcarbonyl include, but are not limited to, (pyridin-3-ylmethyl)carbonyl and (2-(pyrimidin-2-yl)propyl)carbonyl.
The term xe2x80x9cheterocyclealkylsulfonyl,xe2x80x9d as used herein, refers to a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclealkylsulfonyl include, but are not limited to, (pyridin-3-ylmethyl)sulfonyl and (2-(pyrimidin-2-yl)propyl)sulfonyl.
The term xe2x80x9cheterocyclearyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an aryl group, as defined herein. Representative examples of heterocyclearyl include, but are not limited to, 4-(pyridin-3-yl)phenyl and 4-(pyrimidin-2-yl)phenyl.
The term xe2x80x9cheterocyclearylcarbonyl,xe2x80x9d as used herein, refers to a heterocyclearyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclearylcarbonyl include, but are not limited to, 4-(pyridin-3-yl)benzoyl and 4-(pyrimidin-2-yl)benzoyl.
The term xe2x80x9cheterocyclearylsulfonyl,xe2x80x9d as used herein, refers to a heterocyclearyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclearylsulfonyl include, but are not limited to, (4-(pyridin-3-yl)phenyl)sulfonyl and (4-(pyrimidin-2-yl)phenyl)sulfonyl.
The term xe2x80x9cheterocyclecarbonyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, 2-furoyl, morpholin-1-ylcarbonyl, pyridin-3-ylcarbonyl, pyrrolidin-1-ylcarbonyl, and quinolin-3-ylcarbonyl.
The term xe2x80x9cheterocyclecarbonylaryl,xe2x80x9d as used herein, refers to a heterocyclecarbonyl, as defined herein, appended to the parent molecular moiety through an aryl group, as defined herein. Representative examples of heterocyclecarbonylaryl include, but are not limited to, 4-(2-furoyl)phenyl, 4-(1-pyrrolidinylcarbonyl)phenyl, 4-(1-piperidinylcarbonyl)phenyl, 4-(4-morpholinylcarbonyl)phenyl, 4-(1-azetidinylcarbonyl)phenyl, 4-(1-piperazinylcarbonyl)phenyl and 4-(3-pyridinylcarbonyl)phenyl.
The term xe2x80x9cheterocyclecarbonylheterocycle,xe2x80x9d as used herein, refers to a heterocyclecarbonyl, as defined herein, appended to the parent molecular moiety through a heterocycle group, as defined herein. Representative examples of heterocyclecarbonylheterocycle include, but are not limited to, 4-(2-furoyl)-1-piperazinyl, 4-(1-pyrrolidinylcarbonyl)-1-piperazinyl, 4-(1-piperidinylcarbonyl)-1-piperazinyl, 4-(4-morpholinylcarbonyl)-1-piperazinyl, 4-(1-azetidinylcarbonyl)-1-piperazinyl, 4-(1-piperazinylcarbonyl)-1-piperazinyl and 4-(3-pyridinylcarbonyl)-1-piperazinyl.
The term xe2x80x9cheterocycleheterocycle,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through another heterocycle group, as defined herein. Representative examples of heterocycleheterocycle include, but are not limited to, 2-(pyridin-3-yl)thiazo-4-yl and 2-(pyrimidin-2-yl)thiazo-4-yl.
The term xe2x80x9cheterocycleheterocyclecarbonyl,xe2x80x9d as used herein, refers to a heterocycleheterocycle group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocycleheterocyclecarbonyl include, but are not limited to, (2-(pyridin-3-yl)thiazo-4-yl)carbonyl and (2-(pyrimidin-2-yl)thiazo-4-yl)carbonyl.
The term xe2x80x9cheterocycleheterocyclesulfonyl,xe2x80x9d as used herein, refers to a heterocycleheterocycle group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocycleheterocyclesulfonyl include, but are not limited to, (2-(pyridin-3-yl)thiazo-4-yl)sulfonyl and (2-(pyrimidin-2-yl)thiazo-4-yl)sulfonyl.
The term xe2x80x9cheterocycleoxy,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy and quinolin-3-yloxy.
The term xe2x80x9cheterocycleoxyalkyl,xe2x80x9d as used herein, refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycleoxyalkyl include, but are not limited to, pyrid-3-yloxymethyl and 2-quinolin-3-yloxyethyl.
The term xe2x80x9cheterocycleoxyalkylcarbonyl,xe2x80x9d as used herein, refers to a heterocycleoxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocycleoxyalkylcarbonyl include, but are not limited to, (pyridin-3-yloxymethyl)carbonyl and (2-(quinolin-3-yloxy)ethyl)carbonyl.
The term xe2x80x9cheterocycleoxyaryl,xe2x80x9d as used herein, refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an aryl group, as defined herein. Representative examples of heterocycleoxyaryl include, but are not limited to, 4-(pyridin-3-yloxy)phenyl and 4-(quinolin-3-yloxy)phenyl.
The term xe2x80x9cheterocycleoxyarylcarbonyl,xe2x80x9d as used herein, refers to a heterocycleoxyaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocycleoxyarylcarbonyl include, but are not limited to, 4-(pyridin-3-yloxy)benzoyl and 4-(quinolin-3-yloxy)benzoyl.
The term xe2x80x9cheterocycleoxyarylsulfonyl,xe2x80x9d as used herein, refers to a heterocycleoxyaryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocycleoxyarylsulfonyl include, but are not limited to, (4-(pyridin-3-yloxy)phenyl)sulfonyl and (4-(quinolin-3-yloxy)phenyl)sulfonyl.
The term xe2x80x9cheterocyclesulfonyl,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclesulfonyl include, but are not limited to, (pyridin-3-yl)sulfonyl and (quinolin-8-yl)sulfonyl.
The term xe2x80x9cheterocyclethio,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of heterocyclethio include, but are not limited to, pyrid-3-ylsulfanyl and quinolin-3-ylsulfanyl.
The term xe2x80x9cheterocyclethioalkyl,xe2x80x9d as used herein, refers to a heterocyclethio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclethioalkyl include, but are not limited to, pyrid-3-ylsulfanylmethyl, (4-methylpyrimidin-2-yl)sulfanylmethyl, and 2-(quinolin-3-ylsulfanyl)ethyl.
The term xe2x80x9cheterocyclethioalkylcarbonyl,xe2x80x9d as used herein, refers to a heterocyclethioalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclethioalkylcarbonyl include, but are not limited to, (pyrid-3-ylsulfanyl)acetyl, ((4-methylpyrimidin-2-yl)sulfanyl)acetyl, and (quinolin-3-ylsulfanyl)acetyl.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, is hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and 2-ethyl-4-hydroxyheptyl.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein, is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a xe2x95x90O moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a xe2x80x94Oxe2x80x94 moiety.
The term xe2x80x9cphosphono,xe2x80x9d as used herein, refers to a xe2x80x94P(O)(ORD)2 group wherein RD is selected from hydrogen and alkyl, as defined herein. Representative examples of phosphono include, but are not limited to, dimethoxyphosphoryl and diethoxyphosphoryl.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfono,xe2x80x9d as used herein, refers to a xe2x80x94S(O)2(ORE) group wherein RE is selected from alkyl, aryl, and arylalkyl, as defined herein. Representative examples of sulfono include, but are not limited to, methoxysulfonyl, ethoxysulfonyl, (benzyloxy)sulfonyl and phenoxysulfonyl.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a xe2x80x94Sxe2x80x94 moiety.
Preferred compounds of formula I include, but are not limited to:
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}cyclopropanecarboxamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-[(4-methyl-2-pyrimidinyl)sulfanyl]acetamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}nicotinamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzenesulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2-propanesulfonamide;
1-(4-{3-[(3R)-3-aminopyrrolidinyl]propoxy}phenyl)-1-propanone;
(5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione;
(5S)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-methyl-2,4-imidazolidinedione;
(5R)-3-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isopropyl-2,4-imidazolidinedione;
4-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-propanesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-cyanobenzamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
4-bromo-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;
4-chloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-(4-{[((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide;
4-tert-butyl-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide;
3-chloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide;
2-chloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
3-chloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
3,5-dichloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
4-cyano-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
3-cyano-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-methyl-4-sulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide;
5-chloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;
N-(5-{[((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}-4-methyl-1,3-thiazol-2-yl)acetamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide;
4-butoxy-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide;
3-chloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide;
2-cyano-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2,4-difluorobenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-7-isoquinolinesulfonamide;
N-(2-chloro-4-{[((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;
3,4-dichloro-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
4-bromo-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;
4-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methoxybenzenesulfonamide;
4-tert-butyl-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-(trifluoromethyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2,5-dimethoxybenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-methylbenzenesulfonamide;
3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-fluorobenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-ethylbenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-isopropylbenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-fluorobenzenesulfonamide;
2-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
3-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrolidinyl}-3-fluorobenzenesulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-(trifluoromethoxy)benzenesulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-2,4-difluorobenzenesulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-5-isoquinolinesulfonamide;
N-{4-[({(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}amino)sulfonyl]-2-chlorophenyl}acetamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-3,4-dichlorobenzenesulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1H-pyrrole-2-sulfonamide;
N-{(3R)-1-[3-(4-acetylphenoxy)propyl]pyrrolidinyl}-4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-1-methyl-1H-imidazole-4-sulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-thiophenesulfonamide;
5-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methyl-1-benzothiophene-2-sulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,5-bis(trifluoromethyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-quinolinesulfonamide;
4-butoxy-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3,4-dimethoxybenzenesulfonamide;
3-chloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-methylbenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-phenylethenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-2-(trifluoromethoxy)benzenesulfonamide;
2-cyano-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-methylbenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethyl)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-3-fluorobenzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-4-(trifluoromethoxy)benzenesulfonamide;
N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)-8-isoquinolinesulfonamide;
N-(2-chloro-4-{[((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;
3,4-dichloro-N-((3R)-1-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
tert-butyl 1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}-3-pyrrolidinylcarbamate;
4xe2x80x2-{3-[(3R)-3-aminopyrrolidinyl]propoxy}[1,1xe2x80x2-biphenyl]-4-carbonitrile;
tert-butyl (3S)-1-{2-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]ethyl}pyrrolidinylcarbamate
4-methoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
4-isopropyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
4-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
3-cyano-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
1-methyl-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)-1H-imidazole-4-sulfonamide;
3,4-dimethoxy-N-((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)benzenesulfonamide;
N-(2-chloro-4-{[((3R)-1-{3-[4-(2-pyridinyl)phenoxy]propyl}pyrrolidinyl)amino]sulfonyl}phenyl)acetamide;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)pyrrolidinyl]propoxy}[1,1xe2x80x2-biphenyl]-4-carbonitrile;
tert-butyl (3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;
4xe2x80x2-{3-[(3R)-3-(methylamino)pyrrolidinyl]propoxy}[1,1xe2x80x2-biphenyl]-4-carbonitrile;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylacetamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,3,3-trimethylbutanamide;
methyl(3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;
tert-pentyl(3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl(methyl)carbamate;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,Nxe2x80x2,Nxe2x80x2-trimethylurea;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-1-pyrrolidinecarboxamide;
Nxe2x80x2-tert-butyl-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylurea;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-morpholinecarboxamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-methylbenzamide;
4-cyano-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylnicotinamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-furamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;
N-[(3R)-1-[3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl]pyrrolidinyl]-N,Nxe2x80x2,Nxe2x80x2-trimethyl-sulfamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3-fluoro-N-methylbenzenesulfonamide;
4-cyano-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-isopropyl-N-methylbenzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-methyl-4-(methylsulfonyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluoro-N-(4--fluorobenzoyl)benzamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)acetamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-3,3-dimethylbutanamide;
allyl(3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;
methyl(3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;
tert-pentyl(3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinylcarbamate;
Nxe2x80x2-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylurea;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-1-pyrrolidinecarboxamide;
N-(tert-butyl)-Nxe2x80x2-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)urea;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-morpholinecarboxamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-fluorobenzamide;
4-cyano-N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)benzamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)nicotinamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-furamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-(3-pyridinyl)-1,3-thiazole-4-carboxamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-2-propanesulfonamide;
Nxe2x80x2-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N,N-dimethylsulfamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-4-(methylsulfonyl)benzenesulfonamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide;
Nxe2x80x2-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-Nxe2x80x2-(dimethylaminocarbonyl)-N,N-dimethylurea;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(1-pyrrolidinylcarbonyl)-1-pyrrolidinecarboxamide;
N-((3R)-1-{3-[(4xe2x80x2-cyano[1,1xe2x80x2-biphenyl]-4-yl)oxy]propyl}pyrrolidinyl)-N-(4-morpholinylcarbonyl)-4-morpholinecarboxamide;
cyclopropyl{4-[3-(3-hydroxy-1-pyrrolidinyl)propoxy]phenyl}methanone;
cyclopropyl(4-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}phenyl)methanone;
4xe2x80x2-{3-[(3R)-3-hydroxypyrrolidinyl]propoxy}[1,1xe2x80x2-biphenyl]-4-carbonitrile;
4xe2x80x2-[3-(3-oxo-1-pyrrolidinyl)propoxy][1,1xe2x80x2-biphenyl]-4-carbonitrile;
4xe2x80x2-{3-[(3S)-3-hydroxypyrrolidinyl]propoxy}[1,1xe2x80x2-biphenyl]-4-carbonitrile;
4xe2x80x2-[3-(3-hydroxy-3-methyl-1-pyrrolidinyl)propoxy[1,1xe2x80x2-biphenyl]-4-carbonitrile;
4xe2x80x2-[3-(3-hydroxy-3-isopropyl-1-pyrrolidinyl)propoxy][1,1xe2x80x2-biphenyl]-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-hydroxy-3-methylpyrrolidinyl]propoxy}[1,1xe2x80x2-biphenyl]-4-carbonitrile;
N,N-dimethyl-N-[(3R)-1-(3-{[4xe2x80x2-(1-pyrrolidinylcarbonyl)[1,1xe2x80x2-biphenyl]-4-yl]oxy}propyl)pyrrolidinyl]amine;
N,N-dimethyl-N-[(3S)-1-(3-{[4xe2x80x2-(1-pyrrolidinylcarbonyl)[1,1xe2x80x2-biphenyl]-4-yl]oxy}propyl)pyrrolidinyl]amine;
(3R)-1-(3-{[4xe2x80x2-(1-pyrrolidinylcarbonyl)[1,1xe2x80x2-biphenyl]-4-yl]oxy}propyl)-3-pyrrolidinol;
N,N-dimethyl-N-[(3R)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]phenoxy}propyl)pyrrolidinyl]amine;
N,N-dimethyl-N-[(3S)-1-(3-{4-[4-(1-pyrrolidinylcarbonyl)-1-piperazinyl]phenoxy}propyl)pyrrolidinyl]amine;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-methyl-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2-methyl-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3-fluoro-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3xe2x80x2-fluoro-1,1xe2x80x2-biphenyl-4-carbonitrile;
b 4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3 xe2x80x2-methyl-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3xe2x80x2-iodo-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-2xe2x80x2-methyl-1,1xe2x80x2-biphenyl-4-carbonitrile;
3xe2x80x2-chloro-4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3xe2x80x2,5xe2x80x2-difluoro-1,1xe2x80x2-biphenyl-4-carbonitrile;
4xe2x80x2-(3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3xe2x80x2-methoxy-1,1xe2x80x2-biphenyl-4-carbonitrile;
3xe2x80x2-chloro-4xe2x80x2-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-5xe2x80x2-fluoro-1,1xe2x80x2-biphenyl-4-carbonitrile and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
Abbreviations
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: AcOH for acetic acid; BF3OEt2 for boron trifluoride diethyl ether complex; Boc for tert-butoxycarbonyl; (Boc)2O for di-tert-butyl dicarbonate; n-BuLi for n-butyllithium; CDI for 1,1xe2x80x2-carbonyldiimidazole; DCC for 1,3-dicyclohexylcarbodiimide; DMAP for 4-dimethylaminopyridine; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EDCI or EDC for 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; HOBT for 1-hydroxybenzotriazole hydrate; IPA for isopropanol; LAH for lithium aluminum hydride; LDA for lithium diisopropylamide; MeOH for methanol; Ph for phenyl; pyr for pyridine; TFA for trifluoroacetic acid; and THF for tetrahydrofuran.
Preparation of Compounds of the Invention
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-7. 
Sulfonamides of general formula (6), wherein R3, R8, RA, RB, RC and RD are as defined in formula I, and R10 is selected from alkenyl, alkyl, alkynyl, amino, aryl, arylalkenyl, arylalkyl, arylaryl, arylheterocyle, aryloxyaryl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, heterocyclearyl, heterocycleheterocycle, heterocycleoxyaryl or heterocycle, may be prepared as described in Scheme 1. Typically, a compound of general formula (I) can be prepared by a coupling reaction in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine) palladium and a base such as potassium carbonate or cesium carbonate under standard Suzuki, Stille or Heck coupling conditions well known to those of skill in the art. Phenols of general formula (1), obtained commercially or prepared using standard methodology known to those of skill in the art, may be treated with 1-bromo-3-chloropropane (or 1-bromo-2-chloroethane to provide the ethyl analogues) and a base such as potassium carbonate in a solvent such as 2-butanone with heat to provide chlorides of general formula (2). Chlorides of general formula (2) may be treated with tert-butyl pyrrolidinylcarbamate (or tert-butyl (3R)-pyrrolidinylcarbamate or tert-butyl (3S)-pyrrolidinylcarbamate), potassium iodide, a base such as potassium carbonate in a solvent such as 2-butanone with heat to provide N-boc aminopyrrolidines which may be deprotected with acid such as 4N HCl in 1,4-dioxane or trifluoroacetic acid in CH2Cl2 to provide aminopyrrolidines of general formula (3). Aminopyrrolidines of general formula (3) may be treated with sulfonyl chlorides of general formula (4), a base such as triethylamine, diisopropylamine or a polymer supported base such as tris(2-aminoethyl)amine-polystyrene resin and catalytic DMAP in a solvent such as methylene chloride or DMF to provide sulfonamides of general formula (5). Sulfonamides of general formula (5) may be treated with a base such as sodium hydride and an electrophile such as, for example, iodomethane, allyl bromide or propargyl bromide to provide sulfonamides of general formula (6). 
Amides of general formula (9), wherein R3, R9, RA, RB, RC and RD are as defined in formula I and R11 is selected from hydrogen, alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, alkynyloxy, amino, arylalkenyl, arylalkyl, arylaryl, aryl, arylheterocyle, aryloxyaryl, cycloalkylalkyl, cycloalkyl, heterocyclealkyl, heterocyclearyl, heterocycle, heterocycleheterocycle, heterocycleoxyalkyl, heterocycleoxyaryl, and heterocyclethioalkyl, may be prepared as described in Scheme 2. Aminopyrrolidines of general formula (3), from Scheme 1, may be treated with acids of general formula (7), a coupling reagent such as DCC, EDCI, or a polymer supported coupling reagent (N-cyclohexylcarbodiimide, Nxe2x80x2-methyl polystyrene resin), catalytic DMAP, a base such as triethylamine, diisopropylamine or a polymer supported base (tris(2-aminoethyl)amine-polystyrene resin) and optionally HOBT to provide amides of general formula (8). Alternatively, aminopyrrolidines of general formula (3) may be treated with acid chlorides and a base to provide amides of general formula (8). Amides of general formula (8) may be treated with a base such as sodium hydride and an electrophile such as, for example, iodomethane, allyl bromide, propargyl bromide or an acid chloride to provide amides of general formula (9). 
Amines of general formula (10) and (11), wherein R8, RA, RB, RC and RD are as defined in formula I and R3 and R4 are independently selected from alkenyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle and heterocyclealkyl, may be prepared as described in Scheme 3. Aminopyrrolidines of general formula (3), from Scheme 1, may be treated with electrophiles such as, for example, iodomethane, allyl bromide, propargyl bromide, benzylbromide, bromocyclohexane or 3,6-dichloropyridazine and a base such as triethylamine or diisopropylamine in a solvent such as DMF or THF to provide monosubstituted amines of general formula (10). Monosubstituted amines of general formula (10) may be retreated with an electrophile and a base to provide disubstituted amines of general formula (11). 
2,5-Dioxo-1-imidazolidines of general formula (15) and (16), wherein R5, R6, R8, RA, RB, RC and RD are as defined in formula I, may be prepared as described in Scheme 4. Aminopyrrolidines of general formula (3), from Scheme 1, may be treated with N-protected (L) xcex1-amino acids or N-protected (D) xcex1-amino acids of general formula (13), a coupling reagent such as DCC or EDCI and 1-hydroxybenzotriazole hydrate (HOBT) in a solvent such as DMF or methylene chloride to provide amides of general formula (14). Amides of general formula (14) may be deprotected with acid such as 4N HCl in 1,4-dioxane or trifluoroacetic acid in methylene chloride and then treated with 1,1-carbonyldiimidazole (CDI) and a base such as triethylamine or diisopropylamine in a solvent such as acetonitrile to provide 2,5-dioxo-1-imidazolidines of general formula (15). 2,5-Dioxo-1-imidazolidines of general formula (15) may be treated with a base such as sodium hydride and an alkyl halide to provide 2,5-dioxo-1-imidazolidines of general formula (16). 
Alkoxy pyrrolidines of general formula (21), wherein R2, R8, RA, RB, RC and RD are as defined in formula I, may be prepared as described in Scheme 5. Chlorides of general formula (2), from Scheme 1, may be treated with 3-hydroxypyrrolidine (or (3R)-hydroxypyrrolidine or (3S)-hydroxypyrrolidine), a base such as potassium carbonate, and potassium iodide in a solvent such as 2-butanone with heat to provide hydroxy pyrrolidines of general formula (20). Hydroxy pyrrolidines of general formula (20) may be treated with a base such as sodium hydride and alkyl halides, acid chlorides, carbamyl chlorides, sulfonyl chlorides or chlorophosphates in a solvent such as THF or DMF to provide alkoxy pyrrolidines of general formula (21). 
Alkoxy pyrrolidines of general formula (26), wherein R2, R7, R8, RA, RB, RC and RD are as defined in formula I, may be prepared as described in Scheme 6. Chlorides of general formula (2), from Scheme 1, may be treated with 3-pyrrolidinone, a base such as potassium carbonate, and potassium iodide in a solvent such as 2-butanone with heat to provide ketones of general formula (24). Ketones of general formula (24) may be treated with alkyl halides, magnesium metal and 1,2-dibromoethane (or ketones of general formula (24) may be treated with an alkyllithium reagent) in a solvent such as THF or diethyl ether to provide tertiary alcohols of general formula (25). Tertiary alcohols of general formula (25) may be treated with a base such as sodium hydride and an alkyl halide in a solvent such as THF or DMF to provide alkoxy pyrrolidines of general formula (26). 
3-Substituted pyrrolidines of general formula (33), wherein R1, R7, R8, R9, RA, RB, RC and RD are as defined in formula 1, may be prepared as described in Scheme 7. Phenols of general formula (1), from Scheme 1, may be treated with haloketones of general formula (30), a base such as potassium carbonate, and potassium iodide in a solvent such as 2-butanone with heat to provide ketones of general formula (31). Ketones of general formula (31) may be treated with sodium cyanoborohydride under acidic conditions (or other standard reductive-amination conditions) to provide 3-substituted pyrrolidines of general formula (33).
Schemes 1-7 exemplify preparation of compounds of the present invention wherein Z, as defined in formula I, is CH2. Compounds of the present invention wherein Z, as defined in formula I, is a covalent bond may be prepared by using the methods described in schemes 1-7 and substituting 1-bromo-2-chloroethane for 1-bromo-3-chloropropane.
The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.